Proteinopathies, neurodegenerative disorders with protein aggregation-based pathology

Shelkovnikova, Tatyana A.; Kulikova, Alexandra A.; Tsvetkov, P O; Peters, Owen M.; Бачурин, С. О.; Buchman, Vladimir L.; Ninkina, Natalia

doi:10.1134/s0026893312020161

Cited by 57 publications

(30 citation statements)

References 118 publications

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“…neurodegenerative disorders with protein aggregation-based pathology 22 . In healthy cells, these proteins are soluble and do not exhibit pathogenic properties.…”

Section: Discussionmentioning

confidence: 99%

Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates

Garnier

Devred

Byrne

et al. 2017

Sci Rep

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Aggregation of TDP-43 (transactive response DNA binding protein 43 kDa) is a hallmark of certain forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, intracellular TDP-43-positive inclusions are often found in other neurodegenerative diseases. Recently it was shown that zinc ions can provoke the aggregation of endogenous TDP-43 in cells, allowing to assume a direct interaction of TDP-43 with zinc ions. In this work, we investigated zinc binding to the 102–269 TDP-43 fragment, which comprise the two RNA recognition motifs. Using isothermal titration calorimetry, mass spectrometry, and differential scanning fluorimetry, we showed that zinc binds to this TDP-43 domain with a dissociation constant in the micromolar range and modifies its tertiary structure leading to a decrease of its thermostability. Moreover, the study by dynamic light scattering and negative stain electron microscopy demonstrated that zinc ions induce auto-association process of this TDP-43 fragment into rope-like structures. These structures are thioflavin-T-positive allowing to hypothesize the direct implication of zinc ions in pathological aggregation of TDP-43.

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“…neurodegenerative disorders with protein aggregation-based pathology 22 . In healthy cells, these proteins are soluble and do not exhibit pathogenic properties.…”

Section: Discussionmentioning

confidence: 99%

Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates

Garnier

Devred

Byrne

et al. 2017

Sci Rep

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“…An important component in the ALS pathogenesis is the aggregation of proteins prone to conformational changes and the formation of characteristic intracellular histopathological inclu sions, on the basis of which this disease was attributed to the group of proteopathies [1]. In addition to the already known gene SOD1, recent medical genetic studies have identified a number of other genes whose mutations lead to the formation of pathogenic forms of their encoded proteins and development a neurode generative process with motoneuron lesions [2].…”

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confidence: 99%

Gamma-carboline inhibits neurodegenerative processes in a transgenic model of amyotrophic lateral sclerosis

Bronovitsky

Deikin

Ermolkevich

et al. 2015

Dokl Biochem Biophys

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease caused by the selective death of motor neurons. An important component in the ALS pathogenesis is the aggregation of proteins prone to conformational changes and the formation of characteristic intracellular histopathological inclu sions, on the basis of which this disease was attributed to the group of proteopathies [1]. In addition to the already known gene SOD1, recent medical genetic studies have identified a number of other genes whose mutations lead to the formation of pathogenic forms of their encoded proteins and development a neurode generative process with motoneuron lesions [2].In the sporadic ALS forms, these proteins were also found in the histopathological inclusions of the autopsy material of ALS patients. Moreover, studies performed in experimental models of ALS in trans genic mice and cell cultures provided evidence that the pathological picture of proteopathy characteristic of ALS can be reproduced in the case of metabolic disor der of only one of the key proteins [3].When studying the mechanisms of proteopathies associated with ALS and frontotemporal degenera tion, a new type of molecular cellular pathology was described. This pathology is caused by the dysfunction of the DNA/RNA binding proteins TDP43 and FUS (fused in sarcoma), which results in the inability of these proteins to form physiologically active, easily dissociating complexes with RNA (RNP). Instead, these proteins form stable RNA free structures with stably deposited aggregated forms of TDP43 and FUS proteins. This process is accompanied by changes in the intracellular compartmentalization of TDP43 and FUS and their accumulation in the pathogenic inclu sions in the cytoplasm [4][5][6][7].To model the proteopathy with the FUS protein, the aberrant forms of the FUS protein that were able to effectively form protein inclusions in cell cultures, similar to those detected in the autopsy material of ALS patients, were obtained [8]. It was found that the removal of the nuclear localization signal together with the C terminal region, which is significant for the conformational stability of the protein molecule, leads to the development of proteopathy with the involve ment of the FUS protein [5,6]. In the sequences of the gene encoding these protein regions, the largest num ber of mutations association with the hereditary forms of ALS and frontotemporal degeneration was detected. On the basis of such aberrant form of FUS, a transgenic model of proteopathy (fusopathy) was developed. Mice of this transgenic line were charac terized by the formation of histopathological inclu sions in the nervous system tissues and the develop ment of neurodegenerative process accompanied by a progressive loss of motor neurons [9]. These trans genic mice were used in this work to study the neuro protective effect of a compound of the gamma carbo line group on the progression of the model neurode generative process accompanied by primary lesion of motor neurons. It was previously shown t...

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“…Amyloidogenesis is referred to as multifactorial process, however, molecular biological studies conducted in the past decades have shown the leading role of APP in the pathogenesis of the AMD and AD diseases. A number of neurodegenerative disorders have been recently coalesced into a group of proteinopathies because of the similarity of molecular mechanisms underlying their pathogenesis (Skovronsky et al 2006;Shelkovnikova et al 2012). A key step in the development of proteinopathies is a structural change that triggers aggregation of proteins which are prone to form aggregates due to their physical and chemical properties.…”

Section: Introductionmentioning

confidence: 99%

Retinal Degenerative Diseases

2016

Advances in Experimental Medicine and Biology

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Proteinopathies, neurodegenerative disorders with protein aggregation-based pathology

Cited by 57 publications

References 118 publications

Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates

Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates

Gamma-carboline inhibits neurodegenerative processes in a transgenic model of amyotrophic lateral sclerosis

Retinal Degenerative Diseases

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